Scientific exploration of cancer immunotherapy began in the 1950s and the first application relied on polyclonal antibodies. Today, after more than five decades, immunotherapy with monoclonal antibodies continues to offer a promising alternative for cancer treatment (1,2). Several antibodies targeting tyrosine kinase receptors (RTKs) in cancer are currently used in clinical practice (3). The mechanism of action of these antibodies is different in different instances, and—in spite of examples of successful application—often, is poorly understood (4). Bevacizumab and Cetuximab target VEGF-VEGFR and EGF-EGFR, respectively, and act by preventing ligand-receptor interaction, (5,6). Herceptin is a monoclonal antibody specific for HER2, a member of the EGFR family. The mechanism of action underlying Herceptin efficacy is not completely clear but it has been shown that it promotes HER2 degradation, thus decreasing receptor levels at the surface of tumor cells (7).
The MET oncogene, encoding the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF), controls genetic programs leading to cell growth, invasion and protection from apoptosis. Deregulated activation of HGFR is critical not only for the acquisition of tumorigenic properties but also for the achievement of the invasive phenotype (8). The role of MET in human tumors emerged from several experimental approaches and was unequivocally proved by the discovery of MET activating mutations in inherited forms of carcinomas. (9,10). Moreover, HGFR constitutive activation is frequent also in sporadic cancers and studies from this and other laboratories have shown that the MET oncogene is overexpressed in tumors of specific histotypes or is activated through autocrine mechanisms. Besides, the MET gene is amplified in hematogenous metastases of colorectal carcinomas (11). Interfering with Met activation is thus becoming a challenging approach to hamper the tumorigenic and metastatic processes. In the past years, several strategies have been proposed to block aberrant HGFR signalling, targeting either the HGFR itself or its ligand. These approaches include the use of HGF antagonists, HGF neutralizing antibodies, HGFR decoys, small molecule ATP binding site inhibitors of HGFR or small molecules such as geldanamycin, SH2 domain polypeptides and ribozymes (reviewed in 12).